Replicative homeostasis II: influence of polymerase fidelity on RNA virus quasispecies biology: implications for immune recognition, viral autoimmunity and other "virus receptor" diseases

Abstract

Much of the worlds' population is in active or imminent danger from established infectious pathogens, while sporadic and pandemic infections by these and emerging agents threaten everyone. RNA polymerases (RNApol) generate enormous genetic and consequent antigenic heterogeneity permitting both viruses and cellular pathogens to evade host defences. Thus, RNApol causes more morbidity and premature mortality than any other molecule. The extraordinary genetic heterogeneity defining viral quasispecies results from RNApol infidelity causing rapid cumulative genomic RNA mutation a process that, if uncontrolled, would cause catastrophic loss of sequence integrity and inexorable quasispecies extinction. Selective replication and replicative homeostasis, an epicyclical regulatory mechanism dynamically linking RNApol fidelity and processivity with quasispecies phenotypic diversity, modulating polymerase fidelity and, hence, controlling quasispecies behaviour, prevents this happening and also mediates immune escape. Perhaps more importantly, ineluctable generation of broad phenotypic diversity after viral RNA is translated to protein quasispecies suggests a mechanism of disease that specifically targets, and functionally disrupts, the host cell surface molecules--including hormone, lipid, cell signalling or neurotransmitter receptors--that viruses co-opt for cell entry. This mechanism--"Viral Receptor Disease (VRD)"--may explain so-called "viral autoimmunity", some classical autoimmune disorders and other diseases, including type II diabetes mellitus, and some forms of obesity. Viral receptor disease is a unifying hypothesis that may also explain some diseases with well-established, but multi-factorial and apparently unrelated aetiologies--like coronary artery and other vascular diseases--in addition to diseases like schizophrenia that are poorly understood and lack plausible, coherent, pathogenic explanations.

Figure 1

Viral replication, immunological and tissue injury kinetics following acute HCV and HBV infection. Data summated from Figure 1 [29] and modified to represent typical patients with chronic viral persistence. Note: a) High level HCV replication for 6–8 weeks prior to any immune responses, b) onset of humoral immune response well after down-regulation of viral replication [34], and c) transaminase peaks occurs ~ 2weeks later.

Figure 2

Paradoxical HCV replication kinetics. If host immune clearance forces (I_c, black arrows) reduce viral replication acutely (point A), then they must exceed viral expansive forces (V_e, grey arrows) at that point. At equilibrium (e.g. points B through D), viral concentrations (—) and, therefore, viral forces, have fallen by 10^2–3 hence, immune forces I_c must fall by >10^2–3 from A to B for equilibrium to develop. There is no evidence this happens.

Figure 3

Simplified, two dimensional clade diagram of hyperdimensional viral RNA protein sequence-space. Because of RNA_pol (P) infidelity and Müller's ratchet, mutations () are introduced into each RNA template synthesized, and progressively accumulate, resulting in an RNA quasispecies with sequence progressively divergent from consensus sequence. Translation results in a spectrum of proteins (, , , etc.) with properties that also vary progressively from wild-type sequence () to highly variant proteins (, , etc.). Some RNAs will be so abnormal that translation or replication fails or is truncated (), while others will code for grossly defective proteins ( , etc.).

Figure 4

Two-dimensional representation of hyperdimensional RNA (or corresponding protein) frequency distribution curve (scale arbitrary) with conceptual centre of gravity of replication (wild type, green) and variant sequences (blue), zone of reagent specificity (red shading) and threshold of detection (TOD) of any assay. As mutations ( , ) accumulate and RNA sequence progressively diverges from consensus sequence (0) the probability of that RNA sequence and corresponding protein (e.g. envelope, Env.) arising falls rapidly. Standard deviation (σ) of frequency distribution is proportional to RNA_pol fidelity.

Figure 5

Autoregulation of a simple enzyme system: If enzyme E produces either A () or B () and product:enzyme interactions occur such that A:E produce B while B:E favour A, then high initial concentrations of A (or B) will cause rapid synthesis of B (or A). Equilibrium ultimately develops irrespective of starting conditions.

Figure 6

Dynamic progression of RNA_pol functional properties, processivity () and fidelity () predicted by replicative homeostasis. Initial state (A, corresponding to panel A, Figure 7): in a newly infected cell, high-affinity wild-type:RNA_pol interactions will predominate resulting in high RNA_pol processivity but low fidelity causing high-level viraemia with broad virus phenotypic spectrum, maximizing cell tropism. Intracellular accumulation of variant viral proteins (B, c.f. panel B, Figure 7) reduces RNA_pol processivity but increases fidelity reducing viral RNA synthesis and consequently, viraemia before a dynamic, fluctuating equilibrium (C, c.f. panel C or D, Figure 7) develops in which inhibition of RNA_pol by variant viral proteins is balanced by increases in RNA_pol fidelity (with consequent synthesis of wild-type viral products tending to cause high RNA_pol processivity).

Figure 7

Conceptual progression of intracellular viral replication events, including variable RNA_pol fidelity and processivity, restriction of antigenic diversity and immune recognition under influence of Replicative homeostasis. Panels (A->E) changing frequency distribution of viral RNA and protein quasispecies, panels (a->e) cellular events. Initial state (panels A,a) viral replication occurring in cells devoid of molecular inhibitors of RNA_pol high affinity wild-type envelope (Enve, green): RNA_pol interactions predominate, causing rapid low-fidelity viral RNA synthesis and, consequently, a broad spectrum of viral proteins expressed on cell surface at concentrations below TOD. As variant viral proteins accumulate within cells (panel b) and variant viral envelope: RNA_pol interactions increase, RNA_pol fidelity increases while processivity decreases, restricting the distribution of viral RNA and proteins, reducing antigenic display on cells. As variant viral envelope: RNA_pol predominate (panel c), the frequency distribution of expressed viral proteins is restricted so the individual concentration of some proteins increases beyond TOD, allowing immune recognition and polyclonal, low affinity antibodies to develop, blocking cellular egress of viral proteins, further increasing variant viral envelope: RNA_pol interactions, thus immune responses force viruses to reveal wild-type epitopes by restricting antigenic diversity. High affinity responses once developed (panel d) preferentially reduce intracellular concentration of wild-type viral proteins further increasing variant viral envelope: RNA_pol interactions still further restricting RNA_pol processivity to the point of viral latency (panel e).

Figure 8

Cell receptor (R) and normal ligand (L; insulin, PTH, leptin etc.) relationship (1; unbound, 2; activated), receptor permissive for virus cell entry (3) or blocked by polymorphism (Rp, 4). Receptor blockade by variant viral envelope proteins (green E, 5), blockade by antigenic envelope proteins stimulating "autoimmune"response apparently directed against self receptors (E, 6), competitive displacement of antigenic proteins by drug (D, e.g. statin, aspirin) abrogating immune response (7).